The control of both hepatic gluconeogenesis and hepatic mixed function oxidation (drug metabolism) are interrelated and under hormonal control. This interrelationship and its control are greatly affected by diabetes. The overall objective of the proposed research is to determine the nature of these integrated control mechanisms. The specific objectives include the isolation and characterization of a glucagon and diabetes-induced cytosol-located inhibitor of hepatic mixed function oxidation and determination of the mechanism of influence of the gluconeogenic process (as influenced by substrate-type, glucagon and diabetes) on hepatic mixed function oxidation via such factors as competition for NADPH producing substrates, alteration of hepatic redox state and changes in the concentration of known metabolic-intermediate effectors of hepatic mixed function oxidation. Isolated perfused normal and diabetic rat and guinea pig liver will be the focus of the integrated research procedures used to study these control phenomena. Other procedures to be used include in vitro assays with isolated microsomes and various chromatographic techniques. Well characterized model compounds will be used as the mixed function oxidase substrates and common plus unique compounds will be used as the gluconeogenic substrates in these studies. The results of the proposed study will add significantly to our understanding of the fundamentals of metabolic control and interaction and the mechanism(s) through which diabetes affects this interaction. The results of this research will also have direct application to drug therapy. In addition, the proposed research represents the first effort to study any aspect of drug metabolism in diabetic guinea pigs. This is an especially important feature of the proposed research because of certain metabolic (gluconeogenic) and nutritional (ascorbic acid) similarities between guinea pigs and humans.